Most opioid misuse begins during adolescence and young adulthood. Adolescence is the time to intervene with prevention interventions in settings like school-based health centers (HCs), yet few exist that prevent initiation of opioid misuse. ?Serious videogame? interventions can improve health behaviors. They meet adolescents ?where they are,? and compared to standard interventions, they can reach large populations, with consistent fidelity, place limited demands on personnel/resources, facilitate rapid sustainable distribution, all at a potentially lower cost. This proposal harnesses the power of videogame interventions and incorporates components of effective substance use prevention programs to develop an evidence-informed intervention to prevent the initiation of opioid misuse in adolescents. Building on our experience developing videogame interventions and in partnership with the national School-Based Health Alliance (SBHA), we will develop and test a new videogame intervention, PlaySmart. PlaySmart will build upon our PlayForward videogame intervention platform that has demonstrated efficacy in improving attitudes and knowledge related to risk behaviors. Through rigorous formative work and with input from adolescents, and our SBHA and game development partners, we will create the PlaySmart videogame intervention. PlaySmart will be designed to provide players with behavioral skills and knowledge through repetitive and engaging videogame play to target adolescent perception of risk of harm from initiating opioid misuse. The specific aims of this proposal are to: 1) Phase 1 (UG3): Develop and pilot-test the PlaySmart game and, working with SBHA stakeholders, develop implementation strategies and partners; and 2) Phase 2 (UH3): Conduct a randomized controlled trial (RCT) with 532 high-risk 16-19 year old adolescents, in 10 local school-based (HCs), comparing the PlaySmart game to attention/time control games, and work with the SBHA to examine strategies for implementing PlaySmart in school-based HCs nationally. The main outcomes for the RCT will be the proportion of participants who report a perception of great risk of harm from misuse of opioids, intentions to misuse opioids, self-efficacy for refusing opioids, and initiation of opioid misuse. We hypothesize that participants in the PlaySmart group, compared to the control group, will have improved outcomes at 6 weeks (completion of gameplay), and at 3, 6 and 12 months. During the trial, we will collect implementation data from participants and school-based HCs and from the videogame software (e.g. dose). We will use an implementation framework to examine barriers and facilitators to implementing PlaySmart in school-based HCs nationally, and evaluate the cost-effectiveness of the intervention and the cost of the implementation strategies. This research, conducted by an experienced team of videogame intervention researchers and the national SBHA, holds the promise of creating an effective, engaging, and tailored intervention for preventing initiation of opioid misuse. This work has considerable potential for wide implementation, reach, and impact on high-risk adolescents through school-based HCs.